Accelerating the Discovery of Targeted Protein Degraders: Advances in Synthetic Methodologies and Screening Tactics

Targeted protein degradation (TPD) is significantly expanding the druggable landscape to include proteins that are intractable to conventional occupancy-based inhibition. However, the discovery of targeted protein degraders is often less efficient due to their structural complexity and the labor-intensive nature of traditional medicinal chemistry campaigns. To capture the recent advances developed to streamline and accelerate degrader discovery, this review summarizes enabling synthetic methodologies and state-of-the-art screening strategies specialized for this field. From the well-established click chemistry to emerging late-stage functionalization, we highlight a wide array of robust and versatile chemistries that facilitate the rapid construction of diverse degrader libraries. Moreover, we elucidate how these synthetic toolkits synergize with screening tactics to expand the biological space and maximize the efficiency of identifying promising degrader candidates. Furthermore, we underscore that evolving automation and robotic workflows are integrating with these synthetic and screening strategies to propel a new era of degrader discovery. By providing a comprehensive overview and critical perspectives on these advancements, this review aims to offer a practical roadmap for researchers to streamline degrader synthesis and strategically screen their libraries, with the hope of inspiring continued innovation to expedite the discovery of novel degraders with both biological and therapeutic importance.